An enantiocontrolled entry to the tricyclic polar segment of (+)-fusarisetin A

Article abstract of DOI:10.1016/j.tetlet.2015.12.049

The tricyclic polar segment of fusarisetin A, designed for preparing analogues for structure-activity relationship studies of the aliphatic segment thereof, has been constructed in an enantiocontrolled manner, featuring the Yamamoto asymmetric epoxidation of a homoallylic alcohol, C3-selective ring-opening of a 3,4-epoxy alcohol, stereocontrolled merger of a γ-lactone with Garner's counterpart, and ruthenium-catalyzed ring-closing metathesis.

Full text of DOI:10.1016/j.tetlet.2015.12.049

Accepted Manuscript
An enantiocontrolled entry to the tricyclic polar segment of (+)-fusarisetin A
Aki Kohyama, Naoki Kanoh, Eunsang Kwon, Yoshiharu Iwabuchi
PII:
S0040-4039(15)30464-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.049
TETL 47096
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 October 2015
1 December 2015
9 December 2015
Please cite this article as: Kohyama, A., Kanoh, N., Kwon, E., Iwabuchi, Y., An enantiocontrolled entry to the
tricyclic polar segment of (+)-fusarisetin A, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
2015.12.049
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An enantiocontrolled entry to the tricyclic
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Aki Kohyama, Naoki Kanoh, Eunsang Kwon, and Yoshiharu Iwabuchi

1
Tetrahedron Letters
An enantiocontrolled entry to the tricyclic polar segment of (+)-fusarisetin A
Aki Kohyamaa, Naoki Kanoha, Eunsang Kwonb and Yoshiharu Iwabuchia
a Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama 6-3, Sendai 980-8578, Japan
b Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Aobayama 6-3, Sendai 980-8578, Japan.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The tricyclic polar segment of fusarisetin A, designed for preparing analogues for structure–
activity relationship studies of the aliphatic segment thereof, has been constructed in an
enantiocontrolled manner, featuring the Yamamoto asymmetric epoxidation of a homoallylic
alcohol, C3-selective ring-opening of a 3,4-epoxy alcohol, stereocontrolled merger of a -lactone
with Garner’s counterpart, and ruthenium-catalyzed ring-closing metathesis.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords: Fusarisetin A, Yamamoto asymmetric
epoxidation, epoxide ring opening, oxidative
lactonization
Considerable interest has surrounded the fungal metabolite
(+)-fusarisetin A (1), isolated from the soil fungus Fusarium sp.
FN08326, as an emerging class of anticancer agents owing to its
potent inhibitory activity against acinar morphogenesis, cell
migration, and cell invasion in MDAMB-231 cells.1 The
unprecedented complex molecular architecture coupled with a
promising pharmacological properties has spurred intense
synthetic efforts, some of which have culminated in elegant total
syntheses.2 Fascinated by the dense array of polar functional
groups related to tetramic acid class of pharmacophore, our group
also embarked on a synthetic study of fusarisetin A to gain
insight into the structure–activity relationship (SAR) regarding
the aliphatic polycyclic substructure. Herein, we report a concise
entry to the tricyclic polar segment of fusarisetin A, in which the
Yamamoto asymmetric epoxidation3 of a homoallyic alcohol and
Garner’s counterpart4 were employed to secure chiral centers.
allylation. γ-Lactone 6 would be readily accessed from 1,4-diol 7
via the oxidative lactonization. Enantiomerically enriched 1,4-
diol 7 is a logical product of the Yamamoto asymmetric
epoxidation of the corresponding (Z)-homoallylic alcohol3 and
the following regio- and diasteroselective ring opening5 of 3,4-
epoxy alcohol 8 with a TMS-acetylide.
Our retrosynthetic analysis of the polar tricylic segment of
fusarisetin A (1) is depicted in Scheme 1. We set bicyclic lactam-
lactol 3 as the crucial strategic intermediate, the ring closing
metathesis (RCM) of which should provide the tricyclic segments
2a and 2b. 1,3-Diene 2a serves as a platform amenable to extend
additional rings for the SAR via Diels-Alder reaction, and
tricycle 2b can be regarded as the simple polar tricyclic CDE
segment of (+)-fusarisetin A. The construction of 3 would be
attained via the deprotection of 4, the subsequent
transcyclizations, and intramolecular hemiketalization. Foresight
with respect to the inherent diastereopreference of an enolate
derived from -lactone 6 led us to anticipate the stereocontrolled
construction of the quarternary center of 4 via the sequential C-
acylation of 6 with mixed anhydride 54 and subsequent C-
———
Scheme 1. Retrosynthetic analysis
 Corresponding author. Tel.: +81-22-795-6846; fax: +81-22-795-6845; e-mail: y-iwabuchi@m.tohoku.ac.jp

2
Tetrahedron
Scheme 2. Synthesis of chiral lactone
According to the procedure described by Yamamoto and
coworkers,3 commercially available (Z)-pent-3-en-1-ol 9 was
treated with cumene hydroperoxide in toluene from –5 °C (4 h) to
rt (36 h) in the presence of 5 mol% (R,R)-bishydroxamic acid
ligand, 5 mol% Zn(OtBu)4, 10 mol% DMPU, and 4A MS to give
(3R,4S)-epoxyalcohol 8 in 88% with 84% ee. The intended C3-
selective nucleophilic ring opening of epoxide 8 with TMS-
acetylide was best conducted under Yamaguchi conditions using
BF3·THF5a at –78 °C, giving rise to a 4:1 mixture of
regioisomeric acetylene adducts with preference for the 1,4-diol
7. After chromatographic separation, 1,4-diol 7 was treated with
PhI(OAc)2 in the presence of 10 mol% DMN-AZADO6 to furnish
configuration of 13 are confirmed by X-ray crystallography (Fig.
1). On the other hand, after the partial alkyne reduction of 12 to
obtain diene 14, the ring-closing metathesis of which using 2nd
generation Grubbs catalyst furnished 15 in 99% yield.9 Upon the
TBS-protection of the primary hydroxyl group, N-methylation,
and the deprotection of the TBS group, 15 furnished the tricyclic
polar segment 2b.
-lactone
6
in quantitative yield.
After extensive
experimentations, (S)-Garner’s acyl counterpart amenable to
condense with -lactone 6 in a cross-Claisen manner was
identified to be mixed anhydride 5.4a Thus, lithium enolate,
generated in situ by treating 6 with 2 equiv. of LHMDS, was
mixed with 1.2 equiv. of mixed anhydride 5 to give 11 in 54% as
a single diastereomer. Although the use of a stoichiometric excess
LHMDS was essential to conduct efficient condensation of 5 and
6, stereochemical integrity derived from L-serine was completely
retained. The treatment of 11 with allyl bromide in the presence
of K2CO3 in acetone allowed C-allylation in exclusive
stereoselectivity to furnish allylated compound 4 in quantitative
yield (Scheme 2).7
Having assembled all the stereogenic centers and strategic
functionalities, effort was focused on finding an expedient
sequence for constructing the tricyclic polar segment of (+)-
fusarisetin A (Scheme 3). The tasks were ultimately settled by
adopting judicious reaction conditions. Thus, upon exposure to 4
M HCl in dioxane, both Boc and acetonide groups of 4 were
cleanly removed, and the residue obtained by concentrating the
reaction mixture in vacuo was treated with pyridine-toluene to
give bicyclic lactam-lactol 3 in quantitative yield. It should be
noted that introduction of the allyl group at C-3 is essential for
the expedient transcyclization to be operative: attempted
deprotection and lactamization of 11, instead of 4, and following
functionalization was disappointingly low yield due to the base-
labile property of the tetramic acid moiety.
Scheme 3. Synthesis of tricyclic segments 13 and 2b
Preliminary experiments with RCM suggested that the
nonprotected hydroxyl group of the hemiacetal is crucial for
efficient ring-closing eneyne metathesis in this particular case.
As such, after deprotection of the TMS group of 3 under the Pale
conditions using catalytic amount of AgNO3 in CH2Cl2-MeOH-
H2O,8 ring-closing eneyne metathesis of 12 was effected by 2nd
generation Grubbs catalyst to give the tricyclic segment 13 in
84% yield. The stereochemical arrangement and absolute
O
O
N
O
O
Fig. 1 ORTEP drawing of 13 showing thermal ellipsoids at the 50 %
probability level.

3
In conclusion, we have successfully developed a concise
enantiocontrolled entry to the tricyclic polar segment of
fusarisetin A, which would enable the synthesis of various
analogues for SAR studies. Our future work focusing on the
preparation and evaluation of informative sets of derivatives will
be reported in due course.
Acknowledgments
This research is partially supported by the Platform Project for
Supporting in Drug Discovery and Life Science Research
(Platform for Drug Discovery, Informatics, and Structural Life
Science) from Japan Agency for Medical Research and
Development, and Grant-in-Aid for Scientific Research on
Innovative Areas“ Advanced Molecular Transformations by
Organocatalysts” from MEXT, Japan, by a Grant-in-Aid for
Scientific Research (B)(No. 24390001), and by a Grant-in-Aid
for Young Scientists (A)(No. 23689001) from JSPS.
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